Search Results (572)

Serotonin (5-hydroxytryptamine—5-HT) is an important neurotransmitter that exerts a remarkably large array of biological roles in the central nervous system and at the body level. It is involved in generating emotions, being a natural mood stabilizer; it reduces depression, anxiety, modulates sleep, and has many other effects. It is also involved in fetal and postnatal brain development. This variety of biological effects, particularly in the central nervous system, with influence on behavior and cognitive functions, relies on a large number of pre- and postsynaptic serotonin receptor (5-HTR) isoforms spread throughout the brain. They can be grouped in seven large families and include over 18 subtypes, identified based on gene sequences, expression patterns, and pharmacological responses. While in vertebrates these receptors have been properly characterized and described, their correspondents in invertebrates have been far less explored, despite the assumption that they may have similar properties to those described in vertebrates. This paper summarizes the current knowledge in several important areas that together define the entire scope of serotonin receptor research, with a particular emphasis on the role of serotonergic central pathways and circuitry in thermoregulation and correlations with neurologic and psychiatric pathology. Full article

Background: Given the pivotal role of diet in cardiovascular diseases (CVDs), there is a growing demand for new sources of bioactive phytochemicals that can contribute to CVD prevention and treatment. Previous research has unveiled the cardioprotective properties of several parts of sea buckthorn (Hippophae rhamnoides L.). For example, various fractions isolated from raw and roasted sea buckthorn seeds showed antioxidant properties in vitro. In addition, the serotonin-rich fraction obtained from roasted seed extract had the strongest antioxidant activity. However, it was unclear which chemical constituents contribute to the anti-platelet potential of sea buckthorn seeds. Methods: The anti-platelet activity of two fractions (fraction b and fraction c) from raw sea buckthorn seed extract, two fractions (fraction d and fraction g) from roasted sea buckthorn seed extract, and two chemical compounds—isorhamnetin 3-O-β-glucoside-7-O-α-rhamnoside (a major component of fraction b), and serotonin (5-HT, 5-hydroxytryptamine), present in fraction c was estimated in several in vitro assays. Results: Isorhamnetin 3-O-β-glucoside-7-O-α-rhamnoside significantly inhibited platelet activation. It lowered the exposition of the active form of GPIIb/IIIa on the surface of 20 μM ADP-stimulated platelets by about 26%. It also inhibited the exposition of P-selectin on the surface of 10 and 20 μM ADP-stimulated platelets. In addition, isorhamnetin 3-O-β-glucoside-7-O-α-rhamnoside (at 50 µg/mL) significantly prolonged the time of thrombus formation. The results also indicate that fractions d and g (from roasted seeds) are more effective anti-adhesive factors than fractions from raw sea buckthorn seeds. Conclusions: It can be suggested that sea buckthorn seeds can serve as a new source of anti-platelet compounds (especially derivatives of isorhamnetin) beneficial in CVD prevention and treatment; however, in vivo research is needed to clarify their mechanism of action, physiologically relevant concentrations, and therapeutic potential. Full article

Background: Suicide attempts often co-occur with bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCH). Although impairments of the serotonin (5-HT) system have been associated with suicide attempts, it remains unclear whether these alterations reflect suicidal behavior or are confounded by underlying psychiatric diagnosis. This study used a genotype-informed dynamic model of the 5-HT presynapse to disentangle the effects of suicide attempts and psychiatric diagnosis. Methods: We applied a personalized dynamic model of the 5-HT presynapse to 392 psychiatric patients (with BD, MDD, or SCH), categorized by suicide attempt status, and 140 unaffected individuals. The model incorporated five variants across TPH2, SLC6A4, and MAOA genes simulating individual-specific concentration changes of five 5-HT-related molecular species. Model outputs were summarized by six statistical measures (mean, median, maximum, standard deviation, skewness, and kurtosis) and compared across groups. Results: No significant differences were found across groups defined by suicide attempt status and unaffected individuals. However, diagnosis significantly influenced 5-hydroxyindoleacetic acid (5-HIAA) mean, median, maximum, and standard deviation (all p < 0.05). BD patients had lower 5-HIAA levels than SCH patients (mean: p = 0.013; median: p = 0.013; maximum: p = 0.014; standard deviation: p = 0.014). MDD patients also showed lower 5-HIAA levels than SCH patients for the same measures, with differences approaching significance. No significant difference was observed between BD and MDD patients. A diagnosis-by-suicide attempt status interaction was observed for 5-HIAA skewness (p = 0.013). Conclusions: Model-derived 5-HT profiles were shaped primarily by diagnosis, while temporal dynamics of 5-HIAA, rather than its absolute levels, was associated with suicide attempt status. Thus, personalized dynamic modeling incorporating genetic variants may aid in detecting subtle molecular signatures across diagnoses and suicidal behavior. Full article

Background: Selective serotonin reuptake inhibitors (SSRIs) are one of the most frequently used medication classes in psychiatry, with many approved and off-label uses. One common side effect of SSRIs is sexual dysfunction, leading to the off-label use of SSRIs to manage inappropriate sexual behaviors in psychiatric settings. However, no official guidelines exist for this off-label use of SSRIs, so a review of this use is warranted. Methods: This review was conducted using the PubMed and Google Scholar databases. Grey literature was considered for inclusion in this review, but only one report by the United Kingdom’s Care Quality Commission was included. Peer-reviewed references discussing the theoretical mechanisms of SSRI-induced sexual dysfunction, case reports/studies examining the off-label use of SSRIs, and reviews discussing relevant disorders like post-SSRI sexual dysfunction (PSSD) were included in this review. Results: The literature proposes that SSRIs act through a variety of serotonin receptors such as 5-HT_1A, 5-HT_2A, and 5-HT_2C to inhibit dopaminergic tone in the mesolimbic and spinal pathways to cause sexual dysfunction. Discussion: SSRIs are frequently considered for off-label use in managing inappropriate sexual behavior, particularly in geriatric patients with dementia, given their superior safety profile compared to antipsychotics in that population. However, the risk and treatment options for PSSD are unclear, which poses a risk for patients taking SRRIs, as it can be a severe and enduring condition. High-quality clinical trials are needed, as the majority of the literature on the topic consists of case reports or theoretical papers. Full article

Background: Patients with sepsis-associated encephalopathy (SAE) present with cognitive impairments. Serotonergic neurotransmission plays a critical role in regulating cognitive processes, and its dysfunction may contribute to SAE-related deficits. However, the effect of 5-hydroxytryptophan (5-HTP), a direct serotonin precursor, on SAE has not been investigated. We hypothesized that 5-HTP could alleviate cognitive dysfunction in SAE. Methods: The SAE mouse model was induced via intraperitoneal administration of lipopolysaccharide (LPS, 10 mg/kg). Cognitive function and locomotor activity were assessed using the Barnes maze, novel object recognition test, and open-field test to evaluate the effects of 5-hydroxytryptophan (5-HTP). Additionally, WAY100635, a selective 5-HT1A receptor antagonist, was co-administered with 5-HTP to investigate the potential mechanisms underlying its effects on SAE-related cognitive dysfunction. The effects of 5-HTP and WAY100635 on cognition and motor activity were also investigated in healthy mice. Results: LPS-induced sepsis caused a learning deficit. A dose of 10 mg/kg 5-HTP improved cognitive dysfunction, whereas doses of 25 and 100 mg/kg worsened cognitive dysfunction. Moreover, 100 mg/kg 5-HTP increased mortality in SAE mouse models. Neither 5-HTP (10 mg/kg) nor WAY100635 (1 mg/kg) alone exerted a significant impact on the locomotor activity or cognitive function of healthy mice. The cognition-enhancing effect of 5-HTP (10 mg/kg) was reversed by WAY100635 (1 mg/kg). Conclusions: improvement in cognitive dysfunction by 5-HTP suggests that serotonergic transmission plays a role in the pathophysiology of SAE, and 5-HTP, an over-the-counter supplement approved for human use, may hold clinical potential for the prevention and treatment of SAE. Full article

Background/Objectives: This study examined the efficacy of essential amino acid (EAA) supplementation on changes in behavior and hippocampal neurotrophin, dopaminergic and serotonergic markers to a volume overload stress resembling an overtraining syndrome. Methods: Thirty-two 3-month-old male C57Bl/6J mice were randomized into four groups: Resistance training (RT), resistance training with overtraining (RTO), resistance training with overtraining and EAA (RTOEAA), or control. Mice in RTOEAA received EAA supplementation (1.5 g·kg·day⁻¹), while the other groups received a sham treatment. A 5-week resistance training protocol was employed. Training volume was increased two-fold during the final two weeks for RTO and RTOEAA to cause the OTS. EAA intervention for RTOEAA occurred during the OTS. Results: A significant decline in the maximum resistance carrying load in RTO compared to RT (p = 0.002) and RTOEAA (p = 0.029) confirmed that the animals in that group were overtrained. Significantly greater average latency times for RTO compared to RT (p = 0.009) and C (p = 0.05) indicated that the OTS caused spatial memory deficits in animals that were not supplemented. These latter changes may have been related to the significant declines in brain derived neurotrophic (BDNF) expression and elevations in dopamine 1 receptor (D1R) expressions. Increased resiliency for RTOEAA may have been related to the effect of EAA on stimulating significant increases in the expression of hippocampal tyrosine receptor kinase B (TrkB) and serotonin receptors (5-HT1A). Conclusions: EAA supplementation during a resistance model of overtraining appeared to provide increased resiliency to OTS by maintaining neurotrophin expression and enhancing serotonergic adaptation. Full article

Sleep disturbances are linked to metabolic and neurological dysregulation. Moringa oleifera leaves, rich in bioactive compounds, may improve sleep via gut–brain axis modulation. This study investigated the sleep-enhancing effects of fermented Moringa oleifera leaf extract (FM) in mice using metabolomics, gut microbiota analysis, network pharmacology, and molecular docking. A 1:1 combination of Lactobacillus plantarum GDMCC 1.2685 and L. swissii GDMCC 1.791 optimally fermented FM, increasing GABA by 1.67-fold and total amino acids to 46,058.20 ± 845.53 μg/g. FM shortened sleep latency, increased sleep duration, and elevated brain GABA while reducing glutamate (Glu) and Glu/GABA ratios. Hypothalamic metabolomics identified seven sleep-related metabolites, implicating glycerophospholipid, tryptophan, and purine metabolism pathways. FM also reduced Mycobacterium anisopliae (a gut bacterium associated with insomnia) and increased the Firmicutes/Bacteroidetes ratio. Network pharmacology revealed that FM’s effects were mediated via GABA, Glu, and serotonin (5-HT) pathways. These findings demonstrate that FM improves sleep by modulating hypothalamic neurotransmitters and gut microbiota, exerting sedative-hypnotic effects through amino acid, purine, and energy metabolism. Full article

Tryptophan hydroxylase 2 (TPH2) hydroxylates L-tryptophan to L-5-hydroxytryptophan (5-HTP) the first and rate-limiting step of serotonin (5-HT) synthesis in the mammalian brain. Some mutations in the Tph2 gene reducing TPH2 activity are associated with hereditary depressive disorders. The P447R substitution in the mouse TPH2 molecule reduces its thermal stability in vitro and its activity in the brain. The effects of iron ions on thermal stability in vitro and the activity in the brain of the mutant TPH2 were investigated. In the in vitro experiment effects of 0.01, 0.05, and 0.2 mM of FeSO₄ and FeCl₃ on the enthalpy (ΔH) and Gibbs free energy (ΔG) of thermal denaturation of the mutant TPH2 extracted from the midbrain of Balb/c mice were assayed. All FeSO₄ concentrations and 0.05 and 0.2 mM concentrations of FeCl₃ increased these thermodynamic characteristics of the mutant TPH2. Repeated (for 7 days) intramuscular administration of Fe(III) hydroxide dextran complex (15 and 30 mg/kg/day) increased TPH2 activity in the hippocampus, but not in the midbrain in Balb/c mice. Repeated (for 7 days) intramuscular administration of Fe(III) hydroxide dextran complex (15 and 30 mg/kg/day) together with thiamine (8 mg/kg/day) and cyanocobalamin (0.8 mg/kg/day) increased TPH2 activity in the hippocampus, while 30 mg/kg of Fe(III) hydroxide dextran also increased the enzyme activity in the midbrain in Balb/c mice. These results are the first evidence for chaperone-like effects of iron ions on thermal stability in vitro and activity in the brain of the mutant TPH2. Full article

Recent advances in psychedelic research have renewed interest in their therapeutic potential for psychiatric disorders characterized by cognitive and behavioral rigidity. This review examines the rationale for using serotonergic psychedelics—particularly 5-HT₂A receptor agonists such as psilocybin—in the treatment of eating disorders (EDs), including anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). The paper contextualizes these interventions within the broader serotonin hypothesis of EDs, emphasizing serotonergic dysregulation and impaired cognitive flexibility as central features of these conditions. Drawing from animal models, human neuroimaging studies, and emerging clinical trials, the authors outline how psychedelics may promote neuroplasticity and psychological insight through modulation of 5-HT₂A signaling. Preliminary evidence from open-label studies suggests psilocybin may improve ED symptoms and quality of life, though findings are early and methodologically limited. The paper also reviews data on ayahuasca, MDMA, and non-psychedelic serotonergic agents, highlighting both the promise and complexity of psychedelic-assisted therapy in EDs. The authors conclude that while further controlled trials are needed to clarify efficacy, safety, and optimal treatment parameters, psychedelics offer a novel, mechanistically distinct avenue for addressing entrenched ED psychopathology. Full article

Helicobacter pylori infection causes inflammation in the gastric mucosa, and this has been reported to disrupt the gastric microbiota. Serotonin (5-HT) is a key neurotransmitter in the gut–brain axis and plays key roles in intestinal homeostasis and immune function. We investigated gastric serotonin release in H. pylori-infected mice and observed increased release in vaccinated, challenged mice compared to sham vaccinated controls. We investigated the effects of 5-HT on epithelial responses in an in vitro human gastric cancer cell line model (AGS), as well as inflammatory responses and the gastric microbiota in a C57BL/6 mouse model of H. pylori infection. HTR1A was upregulated in the stomachs of mice chronically infected with H. pylori SS1 (3 weeks) compared to uninfected controls, whereas HTR2B was upregulated only in acutely infected mice (3 days), consistent with a role for 5-HT signalling in the development of gastritis. Exposure to 5-HT did not affect NF-κB activation in H. pylori-exposed AGS cells but did inhibit extracellular signal-regulated kinase 1 (ERK1) translocation. Analysis of the gastric microbiota revealed that while vaccination did not significantly affect the diversity of the microbiota, vaccinated animals had increased abundance of Lactobacilli. Our results suggest that local inflammation caused by H. pylori is responsible for increased 5-HT release. Full article

5-HT4 receptors play an important role in the regulation of synaptic plasticity. However, the effect of 5-HT4Rs on neural network activity and intercellular calcium signaling remains enigmatic. Using calcium imaging and original software, we determined the network-level characteristics of calcium dynamics within primary hippocampal cultures. We found that the single activation of 5-HT4 receptors by BIMU8 significantly reduced the correlation of activity within neuron–glial networks of primary cultures, without altering the proportion of active cells or the frequency of calcium events. In contrast, chronic stimulation of 5-HT4Rs promoted greater cell involvement in Ca²⁺ signal generation and increased the frequency of calcium events, while maintaining the connectivity level of the neuron–glial network. Moreover, our immunocytochemical labeling results indicated that chronic stimulation of 5-HT4Rs increased the size of both presynaptic and postsynaptic terminals. The acute blockade of 5-HT4Rs by RS23597-190 exerted a marked inhibitory effect on calcium activity in primary hippocampal cultures. Network connectivity and correlation of calcium activity were disrupted, and the number of functional connections among cells sharply declined. Our study showed that 5-HT4 receptors exhibit diverse effects based on the type and duration of activation, mediating several key functions in regulating neural network calcium activity. Full article

Serotonin and norepinephrine transporters (SERT and NET), located on the presynaptic terminals, regulate serotonergic (5-HT) and noradrenergic (NE) neurotransmission by rapid reuptake of released amines from the synapse. Clinically used antidepressants and highly abused psychostimulants have high affinity for these transporters. The function and expression of SERT and NET are altered in mood disorders and psychostimulant use. Therefore, appropriate functional regulation of SERT and NET is important in maintaining normal homeostasis of 5-HT and NE signaling. Both SERT and NET possess kinase-specific phospho-sites/motifs and exist in phosphorylated state. Several cellular protein kinases and phosphatases regulate the dynamics of phosphorylation of SERT and NET, which in turn determine the subcellular expression and trafficking, microdomain-specific protein–protein interactionsprotein-protein interactions, transporter protein degradation and ultimately transport capacity. Dysregulations in the dynamics of SERT and NET phosphorylation and their impact on functional regulation might contribute to neuropsychiatric disorders. However, the neurobiological consequences and behavioral outcome of SERT and NET phosphorylation in vivo are not fully understood. Studies using intact animal models that directly link the phosphorylation of SERT and NET to regulatory molecular mechanisms and animal behavior are just beginning to emerge. This review summarizes our understanding of the role of phosphorylation-dependent regulation of SERT and NET in animal behaviors relevant to mood and psychostimulant use disorders. Understanding of phosphorylation-dependent molecular mechanisms of SERT and NET regulation is pivotal to identifying potential candidate mechanisms as therapeutic targets in the treatment of neuropsychiatric disorders. Full article

Sedation and anesthesia are essential for ensuring animal welfare during surgical procedures such as hernia repair in swine. However, the number of sedative and anesthetic agents officially approved for livestock use remained limited. This study evaluated the sedative efficacy and serotonergic effects of a romifidine/ketamine/diazepam protocol, with and without the addition of tramadol, in swine undergoing umbilical hernia repair. Sixty-six crossbred Large White swine were randomly allocated to three groups: LL (lidocaine 4 mg/kg by infiltration), LT (lidocaine 2 mg/kg by infiltration + tramadol 2 mg/kg intraperitoneally), and TT (lidocaine2 mg/kg by infiltration + tramadol 4 mg/kg intraperitoneally). The physiological parameters heart rate, arterial pressure, oxygen saturation, rectal body temperature, and respiratory rate were assessed. The depth of intraoperative anesthesia and postoperative sedation was assessed using an ordinal scoring system (0–3). Plasma serotonin (5-HT) concentration was measured at baseline and 24 h post-surgery. Physiological parameters remained within species-specific reference ranges throughout the procedure. Anesthesia depth scores significantly decreased over time in all groups (p ≤ 0.001), with the tramadol-treated groups (LT and TT) showing more prolonged deeper anesthesia. Postoperative sedation was significantly higher in the TT group (p ≤ 0.001). Serotonin concentration decreased in LL, increased in LT, and remained stable in TT. These findings suggest that tramadol may enhance sedation and recovery, potentially through serotonergic modulation. Moreover, serotonin could serve as a physiological marker warranting further investigation in future studies of anesthetic protocols in veterinary medicine. Full article

The serotonergic system, originating in the raphe nuclei, differentially modulates the dorsal and ventral hippocampus, which are implicated in cognition and emotion, respectively. Emerging evidence from rodent models (e.g., neonatal ventral hippocampal lesion, pharmacological NMDA receptor antagonist exposure) and human postmortem studies indicates dorsoventral serotonergic alterations in schizophrenia. These data include elevated 5-HT1A receptor expression in the dorsal hippocampus, linking serotonergic hypofunction to cognitive deficits, and hyperactive 5-HT2A/3 receptor signaling and denser serotonergic innervation in the ventral hippocampus driving local hyperexcitability associated with psychosis and stress responsivity. These dorsoventral serotonergic alterations are shown to disrupt the excitation–inhibition balance, impair synaptic plasticity, and disturb network oscillations, as established by in vivo electrophysiology and functional imaging. Synthesizing these multi-level findings, we propose a novel “dorsoventral serotonin imbalance” model of schizophrenia, in which ventral hyperactivation predominantly contributes to psychotic symptoms and dorsal hypoactivity underlies cognitive deficits. We further highlight promising preclinical evidence that selective targeting of region- and receptor-specific targeting, using both pharmacological agents and emerging delivery technologies, may offer novel therapeutic opportunities enabling symptom-specific strategies in schizophrenia. Full article

The gut microbiota and its interaction with the nervous system through the gut–brain axis (MGB) have been the subject of growing interest in biomedical research. It has been proposed that modulation of microbiota using probiotics could offer a promising therapeutic alternative for mood regulation and the treatment of anxiety and depression disorders. The findings indicate that several probiotic strains, such as Lactobacillus and Bifidobacterium, have demonstrated anxiolytic and antidepressant effects in pre and clinical studies. These effects seem to be mediated by the regulation of the hypothalamic–pituitary–adrenal axis (HPA), the synthesis of neurotransmitters such as serotonin (5-HT) and Gamma-amino-butyric acid (GABA), as well as the modulation of systemic inflammation. However, the lack of standardization in dosing and strain selection, in addition to the scarcity of large-scale clinical studies, limit the applicability of these findings in clinical therapy. Additional research is required to establish standardized therapeutic protocols and better understand the role of probiotics in mental health. The aim of this narrative review is to discuss the relationship between the gut microbiota and the MGB axis in the context of anxiety and depression disorders, the underlying neurobiological mechanisms, as well as the preclinical evidence for the effect of probiotics in modulating these disorders. In this way, an exhaustive search was carried out in scientific databases including PubMed, ScienceDirect, Scopus, and Web of Science. Preclinical research evaluating the effects of different probiotic strains in animal models during chronic treatment was selected, excluding those studies that did not provide access to the full text. Full article